A Center of Biomedical Research Excellence (COBRE) in Pathogen-Host Interactions at Mississippi State University is proposed here. This Center's most innovative component is that all of the junior investigator projects feature hypothesis driven studies to determine molecular mechanisms of pathogen-host interactions using, but all projects also include a systems biology component that will move each of the specific fields under investigation forward in a greater than incremental manner. This COBRE will establish infrastructure such as priority access to an existing Core facility (Omics Biology Lab) and a new virtual core that unifies the most commonly used major equipment in an easily accessible unit. All external and internal mentors reviewed the Junior Investigator projects. The External and Internal Advisory Committee members reviewed and critiqued the overall plan and the administrative core. All of the participants in this COBRE have published at least one paper or have already established a collaboration with another COBRE member, demonstrating that this is a natural team and not a team contrived only for this application. The leadership team and advisory committees for this COBRE have developed a plan for mentoring and accountability that will maximize the probability that the junior investigators will graduate to independent status. The External Advisory Committee includes the P.I. of a nearby COBRE that has graduated 8 R01-funded investigators. The goal of this COBRE is to produce teams that will successfully compete for extramural funding over an extended period of time and will be nationally prominent in their field of investigation. National prominence has already been achieved here in bioinformatics of agricultural species (see, for example, www.agbase.msstate.edu), and this COBRE will be used to leverage this success and apply it to research that is directly related to human health. The topics included in this COBRE represent a wide range of important human pathogens {Streptococcus pneumoniae, influenza virus, Shigella species, Listeria monocytogenes, and Staphylococcus aureus). We expect the combined reductionist and global approach in this COBRE to produce significant progress in research on these pathogens.